Direct Lactonization Research Articles

Birch Reduction of Arenes as an Easy Entry to γ‐Spirolactones

AbstractA convenient method for the synthesis of γ‐spirolactones in only 2–3 steps is described. Birch reduction of inexpensive and commercially available aromatic carboxylic acids in the presence of ethylene oxide affords hydroxy acids, which undergo direct lactonization during work‐up. Suitable precursors are methyl‐substituted benzoic acids, naphthoic, and dicarboxylic acids. Subsequent hydrogenation proceeds smoothly with Pd/C as catalyst and saturated γ‐spirolactones are isolated in excellent yields and stereoselectivities. Thus, up to 3 new stereogenic centers can be constructed as sole diastereomers from achiral benzoic acids. Furthermore, it is possible to control the degree of saturation with Raney nickel or Wilkinson's catalyst to obtain products with 1 double bond. Overall, more than 30 new γ‐spirolactones have been synthesized in analytically pure form.

Aniline‐Type Hypervalent Iodine(III) for Intramolecular Cyclization via C−H Bond Abstraction of Hydrocarbons Containing N‐ and O‐Nucleophiles

AbstractWe developed a method for the preparation of (diacetoxyiodo)‐2‐(N‐alkylamido)benzene as an aniline‐type hypervalent iodine(III). We also achieved direct cyclizations via C−H bond abstraction, such as the Hofmann‐Löffler‐Freytag reaction, a direct amination, and a direct lactonization, using the aniline‐type hypervalent iodine(III) to obtain corresponding products in high yields.magnified image

Cerium(IV) Carboxylate Photocatalyst for Catalytic Radical Formation from Carboxylic Acids: Decarboxylative Oxygenation of Aliphatic Carboxylic Acids and Lactonization of Aromatic Carboxylic Acids.

We found that in situ generated cerium(IV) carboxylate generated by mixing the precursor Ce(OtBu)4 with the corresponding carboxylic acids served as efficient photocatalysts for the direct formation of carboxyl radicals from carboxylic acids under blue light-emitting diodes (blue LEDs) irradiation and air, resulting in catalytic decarboxylative oxygenation of aliphatic carboxylic acids to give C-O bond-forming products such as aldehydes and ketones. Control experiments revealed that hexanuclear Ce(IV) carboxylate clusters initially formed in the reaction mixture and the ligand-to-metal charge transfer nature of the Ce(IV) carboxylate clusters was responsible for the high catalytic performance to transform the carboxylate ligands to the carboxyl radical. In addition, the Ce(IV) carboxylate cluster catalyzed direct lactonization of 2-isopropylbenzoic acid to produce the corresponding peroxy lactone and γ-lactone via intramolecular 1,5-hydrogen atom transfer (1,5-HAT).

Direct lactonization from 1,3-dienes and malonate esters mediated by a combination of iodine and visible light

This manuscript describes the reaction of dienes with carbonyls in the presence of molecular iodine under visible light irradiation to furnish the corresponding butyrolactones with complete site selectivity. The reaction proceeds via site selective sequential addition of iodine radical, which is generated from molecular iodine under visible light irradiation, to dienes to form a reactive intermediate, followed by substitution and cyclization. A variety of dienes and carbonyls are well tolerated under the reaction conditions. This transformation constitutes the first iodine radical-mediated intermolecular lactonization reaction of dienes.

Front Cover: A Concise Approach to Oxo‐Dehydrorotenoid by Direct Lactonization and the Total Syntheses of Stemonone, Rotenonone, 6‐Oxo‐dehydroelliptone, and 6‐Oxo‐6a,12a‐dehydrodeguelin (Eur. J. Org. Chem. 19/2019)

Front Cover: A Concise Approach to Oxo‐Dehydrorotenoid by Direct Lactonization and the Total Syntheses of Stemonone, Rotenonone, 6‐Oxo‐dehydroelliptone, and 6‐Oxo‐6a,12a‐dehydrodeguelin (Eur. J. Org. Chem. 19/2019)

A Concise Approach to Oxo‐Dehydrorotenoid by Direct Lactonization and the Total Syntheses of Stemonone, Rotenonone, 6‐Oxo‐dehydroelliptone, and 6‐Oxo‐6a,12a‐dehydrodeguelin

An approach to construct the oxo‐dehydrorotenoids via direct lactonization of isoflavone‐2‐carboxylic acids is reported. The present reaction proceeds smoothly with good substrate scope and an operationally simple protocol. The application of this method for the total syntheses of the natural products, stemonone, 6‐oxo‐dehydroelliptone, rotenonone, and 6‐oxo‐6a,12a‐dehydrodeguelin, are demonstrated.

Catalytic Dehydrative Lactonization of Allylic Alcohols.

A convenient strategy for the synthesis of phthalides and γ-butyrolactones is reported. The method utilizes readily prepared allylic alcohols in formal Au(I)- and Pd(II)-catalyzed SN2' reactions. Using these catalysts, exclusive formation of the desired five-membered lactones is observed, completely avoiding the competing direct lactonization pathway that forms the undesired seven-membered ring with protic acids and alternative metal salts. This mild and operationally simple method notably tolerates exomethylene groups and should find use in both phthalide and terpene syntheses.

Silver-Catalyzed Intramolecular C(5)–H Acyloxylation of 1,4-Di­substituted 1,2,3-Triazoles

Silver-catalyzed direct lactonization of 1,4-disubstituted 1,2,3-triazole acids through C(5)–H acyloxylation is reported. This method provides a concise and efficient pathway to synthesize lactone-fused triazole derivatives, which were obtained in good to excellent yields at room temperature.

ChemInform Abstract: Direct Oxidative Lactonization of Alkenoic Acids Mediated Solely by NaIO4: Beyond a Simple Oxidant.

AbstractNaIO4 works not only as an oxidant.

ChemInform Abstract: Catalytic Friedel—Crafts/Lactonization Domino Reaction: Facile Access to 3‐Hydroxybenzofuran‐2‐one Scaffold.

A valuable Lewis-acid-catalysed domino reaction involving a Friedel–Crafts alkylation of variously substituted phenols followed by a direct lactonization has been successfully developed (22 examples, yields up to 98 %). This protocol tolerates not only opposite electron demand substituents on the starting materials, but also drastic modifications of the alkylating agents, and gives direct access to the corresponding 3-hydroxy-benzofuran-2-ones, which could easily undergo further chemical transformation. The relevance of our method was further confirmed by the straightforward synthesis of rac-BHFF, the recently discovered and extremely promising positive allosteric modulator of the GABAB receptor.

ChemInform Abstract: Direct Lactonization of α‐Amino γ,δ‐Unsaturated Carboxylic Acid Esters via Olefin Activation: Stereo‐ and Regioselective Production of Homoserine Lactone Scaffolds Having Contiguous Stereocenters.

Abstract Triflic acid-mediated stereoselective direct lactonization of a variety of α-amino γ,δ-unsaturated carboxylic acid esters and the construction of new γ-butyrolactone structural motifs are reported. Several α-amino γ,δ-unsaturated carboxylic acid esters underwent stereo- and regioselective 1,5-cyclization and afforded a variety of highly substituted homoserine lactone scaffolds having contiguous stereocenters. The direct lactonization of the chiral α-amino γ,δ-unsaturated carboxylic acid esters with triflic acid led to the enantioselective synthesis of the novel homoserine lactones. A plausible mechanism for the direct lactonization of α-amino γ,δ-unsaturated carboxylic acid esters is presented. The stereochemistry of major isomers 3f, 7a, 7b, and 7d was unambiguously established from the X-ray structure analysis.

Direct lactonization of α-amino γ,δ-unsaturated carboxylic acid esters via olefin activation: stereo- and regioselective production of homoserine lactone scaffolds having contiguous stereocenters

Triflic acid-mediated stereoselective direct lactonization of a variety of α-amino γ,δ-unsaturated carboxylic acid esters and the construction of new γ-butyrolactone structural motifs are reported. Several α-amino γ,δ-unsaturated carboxylic acid esters underwent stereo- and regioselective 1,5-cyclization and afforded a variety of highly substituted homoserine lactone scaffolds having contiguous stereocenters. The direct lactonization of the chiral α-amino γ,δ-unsaturated carboxylic acid esters with triflic acid led to the enantioselective synthesis of the novel homoserine lactones. A plausible mechanism for the direct lactonization of α-amino γ,δ-unsaturated carboxylic acid esters is presented. The stereochemistry of major isomers 3f, 7a, 7b, and 7d was unambiguously established from the X-ray structure analysis.

Catalytic Friedel–Crafts/Lactonization Domino Reaction: Facile Access to 3‐Hydroxybenzofuran‐2‐one Scaffold

AbstractA valuable Lewis‐acid‐catalysed domino reaction involving a Friedel–Crafts alkylation of variously substituted phenols followed by a direct lactonization has been successfully developed (22 examples, yields up to 98 %). This protocol tolerates not only opposite electron demand substituents on the starting materials, but also drastic modifications of the alkylating agents, and gives direct access to the corresponding 3‐hydroxy‐benzofuran‐2‐ones, which could easily undergo further chemical transformation. The relevance of our method was further confirmed by the straightforward synthesis of rac‐BHFF, the recently discovered and extremely promising positive allosteric modulator of the GABAB receptor.

Synthesis of Mono‐, Di‐, and Tri‐3,4‐dimethoxycinnamoyl‐1,5‐γ‐quinides

AbstractTri‐3,4‐dimethoxycinnamoyl‐1,5‐γ‐quinide was synthesized and fully characterized by a direct synthesis from quinic acid and a large excess of 3,4‐dimethoxycinnamoyl chloride. Mono‐ and di‐3,4‐dimethoxycinnamoyl‐1,5‐γ‐quinides were also obtained from the direct coupling of 1,5‐γ‐quinide and 3,4‐dimethoxycinnamoyl chloride in different molar ratios. Moreover, a hypothetical mechanism of the direct lactonization is proposed.

Direct Lactonization of 2-Arylacetic Acids through Pd(II)-Catalyzed C–H Activation/C–O Formation

Palladium-catalyzed direct lactonization of 2-arylacetic acids through a reaction sequence that includes C-H activation/C-O formation is reported. This method provides a concise and efficient pathway to synthesize fully functionalized benzofuranone derivatives, which are highly relevant to bioactive natural and synthetic products.

Chain Elongation, Macrolactonization, and Hydrolysis of Natural and Reduced Hexaketide Substrates by the Picromycin/Methymycin Polyketide Synthase

Dual action: An analogue of a natural hexaketide thioester substrate is incubated with recombinant picromycin/methymycin synthase (PICS) module 6 with its attached thioesterase (TE). A mixture of 12- and 14-membered-ring macrolactones 10-deoxymethynolide (1) and narbonolide (2) are generated (see scheme) by competing chain elongation and direct lactonization of the substrate. KS=ketosynthase, AT=methylmalonyl transferase, ACP=acyl carrier protein, metmal CoA=methylmalonyl coenzyme A.

The remote-oxyfunctionalization of unactivated carbons in (5 beta)-3-oxobile acids by 2,6-dichloropyridine N-oxide catalyzed by ruthenium-porphyrin and HBr: a direct lactonization at C-20.

Remote-oxyfunctionalization induced by 2,6-dichloropyridine N-oxide (DCP N-oxide) as an oxygen donor and a (5,10,15,20-tetramesitylporphyrinate) ruthenium(II) carbonyl complex (Ru-porphyrin) and HBr as catalysts was examined for a series of methyl ester-peracetylated derivatives of (5 beta)-3-oxobile acids. Using the DCP-N-oxide/Ru-porphyrin/HBr system, 5 beta-hydroxylation predominated for the substrates having a 12-acetoxyl substituent due to steric hindrance, but the presence of a 7-acetoxyl substituent decreased the reactivity of the 5 beta-position allowing for the competitive (20S)-20-oxyfunctionalization, subject to electronic constraints. A variety of novel 5 beta-hydroxylation and (20S)-24,20-gamma-lactonization products, as well as their double-oxyfunctionalization and dehydration products, were obtained in one-step. The alkaline hydrolysis of the gamma-lactones gave the corresponding stereoselective (20S)-20-hydroxy-carboxylic acids.

Direct Lactonization of Alkenols via Osmium Tetroxide Mediated Oxidative Cleavage.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Direct lactonization of alkenols via osmium tetroxide-mediated oxidative cleavage.

[reaction: see text] A highly efficient, mild, and simple protocol is presented for the tandem OsO(4)-mediated oxidative cleavage/oxidative lactonization of alkenols to lactones. The protocol couples the OsO(4)-catalyzed oxidative cleavage of olefins with Oxone as the co-oxidant with the direct oxidation of aldehydes in alcoholic solvents to their corresponding esters.

Intramolecular esterification by lipase powder in microaqueous benzene: Effect of moisture content

In view of the biochemical reaction catalyzed by enzyme powder suspended in a water-insoluble organic solvent, an equation was derived to estimate the amount of water bound to the enzyme powder. With this equation, an apparent adsorption isotherm between free water (water freely dissolved in benzene) and bound water (water bound to crude lipase powder of Pseudomonas fluorescens) was obtained. A direct lactonization reaction (synthesis of cyclopentadenolide from 15-hydroxypen-tadecanoic acid) catalyzed by crude lipase powder of Pseudomonas fluorescens was carried out batchwise in microaqueous benzene at 40oC. A kinetic model of the enzymatic reversible lactonization reaction was derived, from which the effect of moisture content on the initial reaction rate with a fully hydrated enzyme was mathematically expressed. The observed initial reaction rate first increased, then decreased with increasing moisture content, giving rise to the maximum rate at a certain level of the moisture content. The drop in the reaction rate at lower moisture content was due to a lesser hydration of the enzyme molecule (hydration-limited) and the decrease in the reaction rate at higher moisture content was attributed to the dependence of the true initial rate of the reversible reaction on the moisture content (true reversible reaction limited), and could be simulated by the kinetic model. The equilibrium yield approached 100% at a lower moisture content.